Confinement of Kidney Stone Fragments During Lithotripsy

ABSTRACT

The present invention improves significantly the success rate of lithotripsy and reduces the risk of tissue damage, by injecting a temporary plug in front, and optionally behind a concretion (for extracorporeal lithotripsy) or behind a concretion (for intracorporeal lithotripsy). One aspect of the present invention relates to injecting an inverse thermosensitive polymer solution into a lumen, thereby preventing the migration of a concretion, or its fragments, upon extracorporeal or intracorporeal lithotripsy.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/946,478, filed Nov. 15, 2010, which is a continuation of U.S.application Ser. No. 10/963,410, filed Oct. 12, 2004, now abandoned,which claims the benefit of U.S. Provisional Application No. 60/510,505,filed on Oct. 14, 2003. The entire teachings of the above applicationsare incorporated herein by reference.

BACKGROUND OF THE INVENTION

The prevalence of urolithiasis, or kidney stone disease, is increasingwith an aging population. A recent German epidemiology study showed anincrease in the prevalence of kidney stones in the general Germanpopulation from about 0.5% in 1971 to about 1.5% in 2000. (Hesse A. etal. European Urology 2003, 44, 709-713). Urolithiasis is also asignificant health problem in the United States. It is estimated thatbetween 5-10% of the general population will develop a urinaryconcretion during their lifetime. (Pak, C. T. Diseases of the Kidney,5^(th) Edition; Boston; Little, Brown & Co.; 1993; pp. 729-743). Thepeak onset of urolithiasis is typically between 20 and 30 years of age,and males are effected more often then females.

Since being introduced in the 1980s, minimally invasive procedures suchas lithotripsy, as well as ureteroscopy, have become the preferredmethods for treatment in a majority of cases of concretions in theureter, and have a potential for application to concretions that developin other parts of the body such as the pancreas and the gallbladder.Lithotripsy is a medical procedure that uses energy in various formssuch as acoustic shock waves, pneumatic pulsation, electrical hydraulicshock waves, or laser beams to break up biological concretions such asurinary calculi (e.g., kidney stones). The force of the energy, whenapplied either extracorporeally or intracorporeally, usually in focusedand continuous or successive bursts, comminutes a kidney stone intosmaller fragments that may be extracted from the body or allowed to passthrough urination. Applications to other concretions formed in the body,such as pancreatic, salivary and biliary stones as well as the vascularsystem, are currently underway in several research laboratories acrossthe United States and Europe.

As mentioned above, the introduction of extracorporeal shockwavelithotripsy (ESWL) in 1980 changed the management of renal and ureteralcalculous disease from a surgical to a noninvasive procedure. ESWL is aprocedure in which renal and ureteral calculi are broken up into smallerfragments by shock waves. These small fragments then can passspontaneously. All shock wave generators are based on the geometricalprinciple of an ellipse. Shock waves are created at the first focalpoint of an ellipsoid (‘F1’), within the half ellipse, and are directedtowards the second focal point (‘F2’), within the patient. The focalzone is the area at F2 where the shock wave is concentrated. The focalzone of the original Dornier HM3 exceeded 2 cm; most new electromagneticgenerators have focal zones that average only 6 mm. The energy in theseshock waves breaks a larger stone into smaller stones. This noninvasiveapproach allows patients to be rendered stone-free without surgicalintervention or endoscopic procedures.

However there are several complications which can result from standardESWL. Clinical experience demonstrates that a typical fragmentation rateof about 85%, and a stone-free rate of about 65-70%, is achievable withESWL. A major problem with the procedure is that when kidney stones arefragmented the energy is sufficient to widely distribute them throughoutthe ureter and kidney. Further, fragments might become undetectable(e.g., too small to be imaged by fluoroscopy) but still too big to beeasily passed. In addition, after the stones fragment, the shock wavetreatment still focuses on the focal point F2, and the redistribution ofthe stones could move them outside the range of the treatment.Therefore, during the procedure it would be highly beneficial to confinethe kidney stone and the resulting fragments into a narrow space withinthe focal point of F2. An improvement in this approach, which isdescribed herein, would be to place a plug behind and in front of thestone, thereby confining the stone to a particular space. After theprocedure the plugs could be removed and the smaller stones allowed topass.

A different approach to the treatment of kidney stones is intracorporeallithotripsy. A common approach employs laser energy at 2100 nm,generated by a holmium:YAG laser. A coumarin dye laser may also be used.The laser produces a vaporization bubble at the tip of the fiber opticand the energy is transferred to the stone and leads to fragmentation.However, proximal ureteral stone migration during laser lithotripsyaccounts for a high percentage of ureteroscopic failures. In additionthere is an electro-hydraulic technique, which utilizes electricdischarge, ignited between two electrodes disposed within the probe andproducing shock wave, expanding towards the concretion through liquidphase, which surrounds the concretion. Various mechanical anti-migrationbackstops have been developed and involve the placement of these devicesbehind the kidney stone, with respect to the laser or shock wave, andsubsequent extraction of the smaller stones post fragmentation. Asimpler approach, described herein, would be to introduce a temporaryplug behind the stone, preventing the stone and its fragments frommigrating further up the urethra or kidney. This approach would requirea plug that was easily removable after the fragmentation.

It is an object of the invention to facilitate lithotripsy. Theinvention generally includes the use of a material (inversethermosensitive polymers) that exists in liquid form and is transformedinto a gel inside the body of a patient. The inverse thermosensitivepolymers of the invention generally includes the use of a material thatexists in liquid form at temperatures below about body temperature andas a gel at temperatures about at and above body temperature. Thetemperature at which the transition from liquid to gel occurs isreferred to as the inverse thermosensitive polymer, and it can be asmall temperature range as opposed to a specific temperature.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to a method of lithotripsycomprising the steps of: injecting a first composition, comprising aninverse thermosensitive polymer, into a lumen of a mammal, at a firstdistance from a concretion, wherein said first composition does notcontact said concretion; optionally injecting a second composition,comprising an inverse thermosensitive polymer, into said lumen, at asecond distance from said concretion, wherein said second composition isplaced on the approximately opposite side of said concretion relative tosaid first composition, wherein said second composition does not contactsaid concretion; and directing energy to said concretion causing thefragmentation of said concretion into a plurality of fragments.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer is ablock copolymer, random copolymer, graft polymer, or branched copolymer.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer is ablock polymer or a branched copolymer.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer or poloxamine.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isoptionally purified and selected from the group consisting of poloxamine1107, poloxamine 1307, poloxamer 338 and poloxamer 407.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer 407.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymersolution has a transition temperature of between about 10° C. and 40° C.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymersolution has a transition temperature of between about 15° C. and 30° C.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymersolution has a transition temperature of about 25° C.

In certain embodiments, the present invention relates to theaforementioned method, wherein said first distance is between about 1 cmand about 5 cm.

In certain embodiments, the present invention relates to theaforementioned method, wherein said first distance is between about 2 cmand about 4 cm.

In certain embodiments, the present invention relates to theaforementioned method, wherein said first distance is about 3 cm.

In certain embodiments, the present invention relates to theaforementioned method, wherein said second distance is between about 1cm and about 5 cm.

In certain embodiments, the present invention relates to theaforementioned method, wherein said second distance is between about 2cm and about 4 cm.

In certain embodiments, the present invention relates to theaforementioned method, wherein said second distance is about 3 cm.

In certain embodiments, the present invention relates to theaforementioned method, wherein said composition is injected into saidlumen through a percutaneous access device.

In certain embodiments, the present invention relates to theaforementioned method, wherein said composition is injected into saidlumen through a catheter or a syringe.

In certain embodiments, the present invention relates to theaforementioned method, wherein the catheter is a dual lumen catheter ora triple lumen catheter.

In certain embodiments, the present invention relates to theaforementioned method, wherein said energy is an acoustic shock wave, apneumatic pulsation, an electrical hydraulic shock wave, or a laserbeam.

In certain embodiments, the present invention relates to theaforementioned method, wherein said lumen is, or is part of, a kidney, agall bladder, a ureter, a urinary bladder, a pancreas, a salivary gland,a small intestine or a large intestine.

In certain embodiments, the present invention relates to theaforementioned method, wherein said lumen is, or is part of, the ureteror kidney.

In certain embodiments, the present invention relates to theaforementioned method, wherein said concretion is a kidney stone,pancreatic stone, salivary stone, or biliary stone.

In certain embodiments, the present invention relates to theaforementioned method, wherein said concretion is a kidney stone.

In certain embodiments, the present invention relates to theaforementioned method, wherein said mammal is a human.

In certain embodiments, the present invention relates to theaforementioned method, wherein said composition comprises about 5% toabout 30% of said inverse thermosensitive polymer.

In certain embodiments, the present invention relates to theaforementioned method, wherein said composition comprises about 10% toabout 25% said inverse thermosensitive polymer.

In certain embodiments, the present invention relates to theaforementioned method, wherein said composition comprising an inversethermosensitive polymer further comprises a contrast-enhancing agent.

In certain embodiments, the present invention relates to theaforementioned method, wherein said contrast-enhancing agent is selectedfrom the group consisting of radiopaque materials, paramagneticmaterials, heavy atoms, transition metals, lanthanides, actinides, dyes,and radionuclide-containing materials.

In certain embodiments, the present invention relates to theaforementioned method, wherein the inverse thermosensitive polymer has apolydispersity index from about 1.5 to 1.0.

In certain embodiments, the present invention relates to theaforementioned method, wherein the inverse thermosensitive polymer has apolydispersity index from about 1.2 to 1.0.

In certain embodiments, the present invention relates to theaforementioned method, wherein the inverse thermosensitive polymer has apolydispersity index from about 1.1 to 1.0.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer or poloxamine; and said inversethermosensitive polymer solution has a transition temperature of betweenabout 10° C. and 40° C.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer or poloxamine; and said inversethermosensitive polymer solution has a transition temperature of betweenabout 15° C. and 30° C.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer or poloxamine; and said inversethermosensitive polymer solution has a transition temperature of about25° C.

In certain embodiments, the present invention relates to theaforementioned method, wherein said energy is an acoustic shock wave, apneumatic pulsation, an electrical hydraulic shock wave, or a laserbeam; and said lumen is, or is part of, a kidney, a gall bladder, aureter, a urinary bladder, a pancreas, a salivary gland, a smallintestine or a large intestine.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isoptionally purified and selected from the group consisting of poloxamine1107, poloxamine 1307, poloxamer 338 and poloxamer 407; and said lumenis, or is part of, a kidney, a gall bladder, a ureter, a urinarybladder, a pancreas, a salivary gland, a small intestine or a largeintestine.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isoptionally purified poloxamer 407; and said lumen is, or is part of, theureter or kidney.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isoptionally purified and selected from the group consisting of poloxamine1107, poloxamine 1307, poloxamer 338 and poloxamer 407; wherein saidenergy is an acoustic shock wave, a pneumatic pulsation, an electricalhydraulic shock wave, or a laser beam; and said lumen is, or is part of,a kidney, a gall bladder, a ureter, a urinary bladder, a pancreas, asalivary gland, a small intestine or a large intestine.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer or poloxamine; said inversethermosensitive polymer solution has a transition temperature of betweenabout 10° C. and 40° C.; said energy is an acoustic shock wave, apneumatic pulsation, an electrical hydraulic shock wave, or a laserbeam; and said lumen is, or is part of, a kidney, a gall bladder, aureter, a urinary bladder, a pancreas, a salivary gland, a smallintestine or a large intestine.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer or poloxamine; wherein said inversethermosensitive polymer solution has a transition temperature of betweenabout 15° C. and 30° C.; said energy is an acoustic shock wave, apneumatic pulsation, an electrical hydraulic shock wave, or a laserbeam; and said lumen is, or is part of, a kidney, a gall bladder, aureter, a urinary bladder, a pancreas, a salivary gland, a smallintestine or a large intestine.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer or poloxamine; said inversethermosensitive polymer solution has a transition temperature of about25° C.; said energy is an acoustic shock wave, a pneumatic pulsation, anelectrical hydraulic shock wave, or a laser beam; and said lumen is, oris part of, a kidney, a gall bladder, a ureter, a urinary bladder, apancreas, a salivary gland, a small intestine or a large intestine.

In certain embodiments, the present invention relates to theaforementioned method, wherein said inverse thermosensitive polymer isan optionally purified poloxamer or poloxamine; said inversethermosensitive polymer solution has a transition temperature of betweenabout 10° C. and 40° C.; said energy is an electrical hydraulic shockwave; and said lumen is, or is part of, the ureter or kidney.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the deployment of a catheter into a lumen containing aconcretion.

FIG. 2 depicts the deployment of a thermosensitive polymer compositionand the formation of a plug behind the concretion.

FIG. 3 depicts the position of the gel (plug) and concretion beforelithotripsy.

FIG. 4 depicts the deployment of a lithotripsy probe for intracorporeallithotripsy.

FIG. 5 depicts the result of fragmentation of the concretion, whereinthe concretion fragments are prevented from widely distributing throughout the kidney.

FIG. 6 depicts the dissolution of the gel (plug) via the injection of asaline solution into the gel via a catheter.

FIG. 7 depicts the ureter after the dissolution of the gel (plug), withsmall concretion fragments which can easily be passed.

DETAILED DESCRIPTION OF THE INVENTION Overview

The present invention improves significantly the success rate oflithotripsy and reduces the risk of tissue damage, by injectingtemporary plugs in front and behind a concretion (external shock wavelithotripsy) or behind a concretion (intracorporeal lithotripsy). Thepresent invention mitigates the risk of damage to surrounding bodytissue when performing lithotripsy to removing organic material (e.g.,biological concretions such as urinary, biliary, and pancreatic stones)which may obstruct or otherwise be present within the body's anatomicallumens. One aspect of the present invention relates to injecting aninverse thermosensitive polymer solution into a lumen, therebypreventing the migration of a concretion, or its fragments, duringextracorporeal or intracorporeal lithotripsy. In one embodiment, theinvention prevents the upward migration of concretion fragmentsgenerated during a fragmentation procedure. The invention also enablesrepeated or continuous application of energy to a concretion, and itsresulting fragments, or other biological and non-biological/foreignmaterial, while minimizing trauma to the surrounding tissue. The presentinvention improves significantly the success rate of lithotripsy,reduces the risk of tissue damage, and decreases the procedure time.

In one illustrative embodiment according to the disclosure athermosensitive polymer is placed within a lumen at a distance from aconcretion to improve the success rate of a lithotripsy procedure whilereducing the risk of tissue damage. As shown in FIG. 1, a catheter 102is deployed into a lumen 101 containing a concretion 104. Athermosensitive polymer 203 is placed within the lumen 201 using thecatheter 202 at a selected distance from the concretion 204 as depictedin FIG. 2. As depicted in FIG. 3, the placement of the thermosensitivepolymer 303, prior to a lithotripsy procedure, forms a gel plug 303within the lumen 301, when the thermosensitive polymer is at or aboutnormal body temperature. The placement of the gel plug 303 preventsapplied shock waves, or other energy forces, to the concretion 304 frombeing dampened or diverted. According to the disclosure, a lithotripsyprobe 402 is inserted within the lumen 401 to fragment the concretion404 as shown in FIG. 4. The gel plug 403 prevents applied energy frombeing dampened or diverted from the concretion 404.

In another illustrative embodiment energy is applied to the concretionthrough the lithotripsy probe 502. The applied energy results in theconcretion breaking into fragments 505 that are prevented from widelydistributing throughout the kidney by the gel plug 503 placed within thelumen 501, as shown in FIG. 5. After energy is applied and theconcretion is broken into fragments the gel plug 603 within the lumen601 is dissolved by the injection of a low temperature saline solutioninto the gel plug 603 through a catheter 602, as depicted in FIG. 6. Theinjection of the low temperature saline solution dissolves the gel plugallowing small concretion fragments 705 to pass through the lumen 701 asshown in FIG. 7.

DEFINITIONS

For convenience, certain terms employed in the specification,exemplification, and appended claims are collected here.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The terms “reversibly gelling” and “inverse thermosensitive” refer tothe property of a polymer wherein gelation takes place upon an increasein temperature, rather than a decrease in temperature.

The term “transition temperature” refers to the temperature ortemperature range at which gelation of an inverse thermosensitivepolymer occurs.

The term “contrast-enhancing” refers to materials capable of beingmonitored during injection into a mammalian subject by methods formonitoring and detecting such materials, for example by radiography orfluoroscopy. An example of a contrast-enhancing agent is a radiopaquematerial. Contrast-enhancing agents including radiopaque materials maybe either water soluble or water insoluble. Examples of water solubleradiopaque materials include metrizamide, iopamidol, iothalamate sodium,iodomide sodium, and meglumine Examples of water insoluble radiopaquematerials include metals and metal oxides such as gold, titanium,silver, stainless steel, oxides thereof, aluminum oxide, zirconiumoxide, etc.

As used herein, the term “polymer” means a molecule, formed by thechemical union of two or more oligomer units. The chemical units arenormally linked together by covalent linkages. The two or more combiningunits in a polymer can be all the same, in which case the polymer isreferred to as a homopolymer. They can be also be different and, thus,the polymer will be a combination of the different units. These polymersare referred to as copolymers.

The term “biocompatible”, as used herein, refers to having the propertyof being biologically compatible by not producing a toxic, injurious, orimmunological response in living tissue.

The term “poloxamer” denotes a symmetrical block copolymer, consistingof a core of PPG polyoxyethylated to both its terminal hydroxyl groups,i.e. conforming to the interchangeable generic formula(PEG)_(X)-(PPG)_(Y)-(PEG)_(X) and (PEO)_(X)—(PPO)_(Y)—(PEO)_(X). Eachpoloxamer name ends with an arbitrary code number, which is related tothe average numerical values of the respective monomer units denoted byX and Y.

The term “poloxamine” denotes a polyalkoxylated symmetrical blockcopolymer of ethylene diamine conforming to the general type[(PEG)_(X)-(PPG)_(Y)]₂-NCH₂CH₂N-[(PPG)_(Y)-(PEG)_(X)]₂. Each Poloxaminename is followed by an arbitrary code number, which is related to theaverage numerical values of the respective monomer units denoted by Xand Y.

The term “inverse thermosensitive polymer” as used herein refers to apolymer that is soluble in water at ambient temperature, but at leastpartially phase-separates out of water at physiological temperature.Inverse thermosensitive polymers include poloxamer 407, poloxarner 188,Pluronic® F127, Pluronic® F68, poly(N-isopropylacrylamide), poly(methylvinyl ether), poly(N-vinylcaprolactam); and certainpoly(organophosphazenes). See Bull. Korean Chem. Soc. 2002, 23, 549-554.

The phrase “polydispersity index” refers to the ratio of the “weightaverage molecular weight” to the “number average molecular weight” for aparticular polymer; it reflects the distribution of individual molecularweights in a polymer sample.

The phrase “weight average molecular weight” refers to a particularmeasure of the molecular weight of a polymer. The weight averagemolecular weight is calculated as follows: determine the molecularweight of a number of polymer molecules; add the squares of theseweights; and then divide by the total weight of the molecules.

The phrase “number average molecular weight” refers to a particularmeasure of the molecular weight of a polymer. The number averagemolecular weight is the common average of the molecular weights of theindividual polymer molecules. It is determined by measuring themolecular weight of n polymer molecules, summing the weights, anddividing by n.

The term “concretion” denotes a mass or nodule of solid matter formed bygrowing together, by congelation, condensation, coagulation, induration,etc. Common synonyms, for example, are stones, clots, tones, lumps orcalculi. Often, biologically, a concretion is a hard lump of mineralsalts found in a hollow organ or duct of the body. In one embodiment,concretion refers to stone-like objects found within a body organ (e.g.,the kidneys).

The term “lumen” denotes the space enclosed by a tube-like structure orhollow organ, such as inside an artery, a vein, a kidney, a gallbladder, a ureter, a urinary bladder, a pancreas, a salivary gland, asmall intestine or a large intestine (i.e., an opening, space, or cavityin a biological system).

Concretions

Concretions can develop in certain parts of the body, such as in thekidneys, pancreas, ureter and gallbladder. It is not uncommon forbiological concretions to be referred to as calculi or stones,especially when they are composed of mineral salts. For example,concretions formed in the biliary system are called gallstones. Thosethat form in the bladder are as also known as vesical calculi or bladderstones, and cystoliths. Calculi occurring in the kidney are often calledkidney stones. Calculi can also occur in the ureter and are usually theresult of the passage of one originating in the kidney. Calculi of theurinary bladder; also known as vesical calculi or bladder stones, andcystoliths. It is also possible to observe the presence of calculi in asalivary ducts or glands.

There are four main types of calculi observed biologically. The majorityof calculi, about 75%, are calcium-containing, composed of calciumoxalate, sometimes mixed with calcium phosphate. Another 15% arecomposed of magnesium ammonium phosphate; these calculi are oftenreferred to as “triple stones” or struvite stones. The bulk of theremaining stones are made up of uric acid or cystine. When these calculiare too large to pass spontaneously, medical intervention is oftenneeded.

Lithotripsy

Larger biological concretions often need to be shattered because theirsize prohibits non-surgical removal from the body. This procedure isknown as lithotripsy. Shattering a concretion (by, for example, light,chemical, or physical energy) will disperse the resulting fragments fromthe original location of the concretion. It is important to remove allthe fragments, as fragments that are not removed from the body can formthe nuclei for the formation of new concretions. This process is madedifficult by the fact that often the shattering process can causefragments to move into inaccessible or unknown areas of the body thuspreventing or interfering with the capture and removal of the fragments.

It is common to refer to lithotripsy with respect to where the energy isgenerated. Extracorporeal lithotripsy is where the energy needed isgenerated outside the body; intracorporeal lithotripsy is where theenergy needed is generated inside the body; both methods are discussedin more detail below.

Extracorporeal Lithotripsy

In one embodiment, energy transferred to fragment a concretion mayemanate from outside the patient's body, from a lithotriptor forexample, and travel through the patient's body until reaching theconcretion targeted for fragmentation in a process called extracorporealshock wave lithotripsy (ESWL). ESWL is a method of stone fragmentationcommonly used to treat kidney stone disease. Various lithotriptors andmethods exist for generating high-intensity, focused shock waves for thefragmentation of objects, such as kidney stones, inside a human beingand confined in a body liquid. A lithotriptor generating a spark gapdischarge in water has been used to generate a shock wave within anellipsoidal reflector, which couples and focuses the shock wave tofragment kidney stones inside the patient's body. Lithotriptors alsoexist that use a coil and a mating radiator, in the form of a sphericalsegment, to produce magnetically induced self-converging shock wavesthat can be directed at a stone within the patient's body. Alithotriptor also exists that features piezoelectric elements arrangedin mosaic form on a spheroidal cap have also been used to producefocused high-intensity shock waves at the geometric center of the cap,where the concretion must be placed.

The treatment of concretion ailments by means of an extracorporeallithotripsy apparatus requires some means, such an ultrasound locatingsystem, for correctly positioning the lithotripsy apparatus and thepatient relative to each other so that the concretion, such as a kidneystone, is located in the focus of the shock waves. The focused shockwaves are then coupled into the body of the patient, and act on theconcretion to disintegrate it into fragments, which can be naturallyeliminated.

As mentioned above, a locating system is also needed to identifying theposition of the concretion within the patient, such as an x-ray systemor an ultrasound system. A visual display is provided by the locatingsystem which includes a mark identifying the concretion and an indicatorfor the position of the focus. Devices of this type are utilized, forexample, for disintegrating kidney stones in situ in the human body, andhave the advantage of avoiding invasion of the body using instruments.

Intracorporeal Lithotripsy

Intracorporeal lithotripsy utilizes a probe advanced with the aim ofendoscope and positioned in proximity to the concretion. The energy,required for fragmentation is transferred through the probe to theconcretion and the treatment process is visualized during fragmentation.The mode of energy transfer may be different and accordingly theintracorporeal lithotripsy techniques are divided into following groups:ultrasonic, laser, electro-hydraulic and mechanic/ballistic impact.

The last group comprises, for example, detonating an explosive near theconcretion and causing the shock wave generated by the explosion to actdirectly upon the concretion and crush it into pieces. An example ofsuch technique is disclosed in U.S. Pat. No. 4,605,003, referring to alithotriptor comprising an inner tube inserted within an outer slendertube and provided with an explosive layer or a gas-generating layer. Bythe blasting of the explosive layer or the gas-generating layer, theouter slender tube or the inner tube is caused to collide with the stoneand crush it.

An example of mechanical impact technique can be found in U.S. Pat. No.5,448,363 in which is disclosed an endoscopic lithotriptor provided witha hammer element to periodically strike the concretion. The hammerelement is pneumatically driven by a linear jet of air causing it toswing through an arc about a pivot to impact an anvil. There are knownalso many other patents, disclosing lithotriptors, which operation isbased on mechanic/ballistic principle, e.g. U.S. Pat. No. 5,722,980 andU.S. Pat. No. 6,261,298.

An example of laser technique is a multi-purpose lithotriptor, equippedwith laser light-conducting fibers, through which the energy requiredfor crushing the concretion is conducted.

Ultrasonic technique is relatively popular and because of its safety andusefulness is widely accepted. According to this principle ultrasoundprobe emits high-frequency ultrasonic energy that has a disruptioneffect upon direct exposure to the concretion. Direct contact of theprobe tip and stone is essential for effectiveness of ultrasoniclithotripsy. This technique is implemented in many lithotriptors, e.g.as described in U.S. Pat. No. 6,149,656.

In addition there is electro-hydraulic technique, which utilizeselectric discharge, ignited between two electrodes disposed within theprobe and producing shock wave, expanding towards the concretion throughliquid phase, which surrounds the concretion. In the literatureelectro-hydraulic lithotripsy is defined as the oldest form of “power”lithotripsy. The electro-hydraulic lithotriptor releases high-energyimpulse discharges from an electrode at the tip of a flexible probe,which is placed next to the stone. It is considered a highly effectivemeans of bladder stone shattering and has become an accepted practicefor this use. Since the shock waves generated during electro-hydrauliclithotripsy treatment are of sufficient force the probe must not be used5 mm or closer to soft tissues otherwise severe damage will result.Since the discharge takes place within liquid phase the concretion isdestroyed by virtue of combination of energy of the shock wave, causedby the discharge, hydraulic pressure of the surrounding liquid andcollision of fragments in the liquid flow.

Problems with Conventional Lithotripsy

It can be easily appreciated that in lithotripsy the energy istransferred indirectly to the concretion via a liquid medium. Thereforethe amount of energy required for fragmentation must be sufficient toovercome the strength of the concretion, to cause its fragmentation,after the energy has been delivered through the working liquid. For aconcretion encased in a polymer matrix, even more additional energy willbe needed. Unfortunately, release of such high levels of energy byproducing shock waves might be harmful to the adjacent tissues andtherefore potentially dangerous for the patient.

Another problem of almost all lithotriptors that are intended fordestroying concretions by bringing mechanical energy of impact or shockwave is the fact that the stone is usually “displaced” with each pulseof energy, leaving the previous place and being “thrown” to another one.This renders the operation complicate and may cause mechanical damage tothe surrounding tissue. The instant invention solves both of theseproblems.

Methods of the Invention

The present invention improves significantly the success rate oflithotripsy and reduces the risk of tissue damage, by injectingtemporary plugs in front and behind a concretion (external shock wavelithotripsy) or behind a concretion (intracorporeal lithotripsy) priorto the fragmentation of the concretion. The plugs in both applicationsconsist of an aqueous solution of inverse thermosensitive polymers.These polymer solutions are liquid below body temperature and gel atabout body temperature. The polymer solution starts externally of thebody and thus at a temperature below body temperature. The polymersolution may be further chilled to prolong the time the gel stays in theliquid form. A preferred temperature is about 10° C. below the gelationtemperature of the polymer solution.

Introduction/Removal of the Plug

The polymer solution can be introduced through a catheter behind and infront of the concretion for extracorporeal shockwave lithotripsyapproach, and just behind the concretion for the intracorporeallithotripsy approach. In one embodiment, a catheter can be used todispense one or more fluids other than or in addition to the inversethermosensitive polymer. The catheter also can be a dilatation catheterwith the ability also to dispense one or more fluids other than or inaddition to the polymer. In one embodiment, the catheter is 3-10 Frenchin size, and more preferably 3-6 French.

In another embodiment the catheter may be a triple lumen catheter withone lumen for the delivery of the polymer solution behind the kidneystone, one lumen for the delivery of the polymer solution in front ofthe kidney stone and one lumen for the delivery of other fluids likecontrast agent solution, saline or for the delivery of a solution todissolved the gel after the procedure.

In another embodiment, the syringe or other mechanism used to inject theinverse thermosensitive polymer in liquid form into the body can be, forexample, a 1-100 cc syringe such as a syringe with volume of 1-50 cc orwith a volume of 1-5 cc. Pressure applied to the syringe can be appliedby hand or by an automated syringe pusher.

The gelation of reverse thermosensitive polymers is dependent on thetemperature and the concentration of the polymer. Therefore, after thefragmentation procedure, the gel can be removed by instilling a fluidaround the gel, which leads to dissolution of the gel. The fluid may bechilled to help in the dissolution with a preferred temperature of about10° C. below the gelation temperature. The fluid can be instilledthrough a catheter or syringe percutaneously.

Inverse Thermosensitive Polymers

In general, the inverse thermosensitive polymers used in the methods ofthe invention, which become a gel at or about body temperature, can beinjected into the patient's-body in a liquid form. The injected materialonce reaching body temperature undergoes a transition from a liquid to agel. The inverse thermosensitive polymers used in connection with themethods of the invention may comprise a block copolymer with inversethermal gelation properties. The block copolymer can further comprise apolyoxyethylene-polyoxypropylene block copolymer such as abiodegradable, biocompatible copolymer of polyethylene oxide andpolypropylene oxide. Also, the inverse thermosensitive polymer caninclude a therapeutic agent such as an anti-angiogenic agent.

The molecular weight of the inverse thermosensitive polymer ispreferably between 1,000 and 50,000, more preferably between 5,000 and35,000. Preferably the polymer is in an aqueous solution. For example,typical aqueous solutions contain about 5% to about 30% polymer,preferably about 10% to about 25%. The molecular weight of a suitableinverse thermosensitive polymer (such as a poloxamer or poloxamine) maybe, for example, between 5,000 and 25,000, and more particularly between7,000 and 20,000.

The pH of the inverse thermosensitive polymer formulation administeredto the mammal is, generally, about 6.0 to about 7.8, which are suitablepH levels for injection into the mammalian body. The pH level may beadjusted by any suitable acid or base, such as hydrochloric acid orsodium hydroxide.

Suitable inverse thermosensitive polymers includepolyoxyethylene-polyoxypropylene (PEO-PPO) block copolymers. Twoexamples are Pluronic® F127 and F108, which are PEO-PPO block copolymerswith molecular weights of 12,600 and 14,600, respectively. Each of thesecompounds is available from BASF of Mount Olive, N.J. Pluronic® F108 at12-25% concentration in phosphate buffered saline (PBS) is an example ofa suitable inverse thermosensitive polymeric material. Pluronic® acidF127 at 12-25% concentration in PBS is another example of a suitablematerial. Low concentrations of dye (such as crystal violet), hormones,therapeutic agents, fillers, and antibiotics can be added to the inversethermosensitive polymer. In general, other biocompatible, biodegradablePEO-PPO block copolymers that exist as a gel at body temperature and aliquid at below body temperature may also be used according to thepresent invention.

Notably, Pluronic® polymers have unique surfactant abilities andextremely low toxicity and immunogenic responses. These products havelow acute oral and dermal toxicity and low potential for causingirritation or sensitization, and the general chronic and sub-chronictoxicity is low. In fact, Pluronic® polymers are among a small number ofsurfactants that have been approved by the FDA for direct use in medicalapplications and as food additives (BASF (1990) Pluronic® & Tetronic®Surfactants, BASF Co., Mount Olive, N.J.). Recently, several Pluronic®polymers have been found to enhance the therapeutic effect of drugs, andthe gene transfer efficiency mediated by adenovirus. (March K L, MadisonJ E, Trapnell B C, “Pharmacokinetics of adenoviral vector-mediated genedelivery to vascular smooth muscle cells: modulation by poloxamer 407and implication for cardiovascular gene therapy” Hum Gene Therapy 1995,6, 41-53).

The average molecular weights of the poloxamers range from about 1,000to greater than 16,000 daltons. Because the poloxamers are products of asequential series of reactions, the molecular weights of the individualpoloxamer molecules form a statistical distribution about the averagemolecular weight. In addition, commercially available poloxamers containsubstantial amounts of poly(oxyethylene) homopolymer andpoly(oxyethylene)/poly(oxypropylene diblock polymers. The relativeamounts of these byproducts increase as the molecular weights of thecomponent blocks of the poloxamer increase. Depending upon themanufacturer, these byproducts may constitute from about 15 to about 50%of the total mass of the polymer.

The inverse thermosensitive polymers may be purified using a process forthe fractionation of water-soluble polymers, comprising the steps ofdissolving a known amount of the polymer in water, adding a solubleextraction salt to the polymer solution, maintaining the solution at aconstant optimal temperature for a period of time adequate for twodistinct phases to appear, and separating physically the phases.Additionally, the phase containing the polymer fraction of the preferredmolecular weight may be diluted to the original volume with water,extraction salt may be added to achieve the original concentration, andthe separation process repeated as needed until a polymer having anarrower molecular weight distribution than the starting material andoptimal physical characteristics can be recovered.

In certain embodiments, a purified poloxamer or poloxamine has apolydispersity index from about 1.5 to about 1.0. In certainembodiments, a purified poloxamer or poloxamine has a polydispersityindex from about 1.2 to about 1.0. In certain embodiments, a purifiedpoloxamer or poloxamine has a polydispersity index from about 1.1 toabout 1.0.

The aforementioned process consists of forming an aqueous two-phasesystem composed of the polymer and an appropriate salt in water. In sucha system, a soluble salt can be added to a single phase polymer-watersystem to induce phase separation to yield a high salt, low polymerbottom phase, and a low salt, high polymer upper phase. Lower molecularweight polymers partition preferentially into the high salt, low polymerphase. Polymers that can be fractionated using this process includepolyethers, glycols such as poly(ethylene glycol) and poly(ethyleneoxide)s, polyoxyalkylene block copolymers such as poloxamers,poloxamines, and polyoxypropylene/polyoxybutylene copolymers, and otherpolyols, such as polyvinyl alcohol. The average molecular weight ofthese polymers may range from about 800 to greater than 100,000 daltons.See U.S. Pat. No. 6,761,824. The aforementioned purification processinherently exploits the differences in size and polarity, and thereforesolubility, among the poloxamer molecules, the poly(oxyethylene)homopolymer and the poly(oxyethylene)/poly(oxypropylene) diblockbyproducts. The polar fraction of the poloxamer, which generallyincludes the lower molecular weight fraction and the byproducts, isremoved allowing the higher molecular weight fraction of poloxamer to berecovered. The larger molecular weight poloxamer recovered by thismethod has physical characteristics substantially different from thestarting material or commercially available poloxamer including a higheraverage molecular weight, lower polydispersity and a higher viscosity inaqueous solution.

Other purification methods may be used to achieve the desired outcome.For example, WO 92/16484 discloses the use of gel permeationchromatography to isolate a fraction of poloxamer 188 that exhibitsbeneficial biological effects, without causing potentially deleteriousside effects. The copolymer thus obtained had a polydispersity index of1.07 or less, and was substantially saturated. The potentially harmfulside effects were shown to be associated with the low molecular weight,unsaturated portion of the polymer, while the medically beneficialeffects resided in the uniform higher molecular weight material. Othersimilarly improved copolymers were obtained by purifying either thepolyoxypropylene center block during synthesis of the copolymer, or thecopolymer product itself (e.g., U.S. Pat. No. 5,523,492 and U.S. Pat.No. 5,696,298).

Further, a supercritical fluid extraction technique has been used tofractionate a polyoxyalkylene block copolymer as disclosed in U.S. Pat.No. 5,567,859. A purified fraction was obtained, which was composed of afairly uniform polyoxyalkylene block copolymer having a polydispersityof less than 1.17. According to this method, the lower molecular weightfraction was removed in a stream of carbon dioxide maintained at apressure of 2200 pounds per square inch (psi) and a temperature of 40°C.

Additionally, U.S. Pat. No. 5,800,711 discloses a process for thefractionation of polyoxyalkylene block copolymers by the batchwiseremoval of low molecular weight species using a salt extraction andliquid phase separation technique. Poloxamer 407 and poloxamer 188 werefractionated by this method. In each case, a copolymer fraction wasobtained which had a higher average molecular weight and a lowerpolydispersity index as compared to the starting material. However, thechanges in polydispersity index were modest and analysis by gelpermeation chromatography indicated that some low-molecular-weightmaterial remained. The viscosity of aqueous solutions of thefractionated polymers was significantly greater than the viscosity ofthe commercially available polymers at temperatures between 10° C. and37° C., an important property for some medical and drug deliveryapplications. Nevertheless, some of the low molecular weightcontaminants of these polymers are thought to cause deleterious sideeffects when used inside the body, making it especially important thatthey be removed in the fractionation process. As a consequence,polyoxyalkylene block copolymers fractionated by this process are notappropriate for all medical uses.

In a preferred embodiment, the polymers used are block polymers such aspolyoxyethylene-polyoxypropylene (PEO-PPO) block polymers of the generalstructure A-B, A-B-A (e.g., Pluronic®), or (A-B-A), with A being the PEOpart and B being the PPO part and n being greater than 1. In anotherpreferred embodiment, the polymers used are branched polymers ofpolyoxyethylene-polyoxypropylene (PEO-PPO) like tetra-functionalpoloxamines (e.g., Tetronic®).

EXEMPLIFICATION Example 1 Gelation Temperature of Selected Pluronic® andTetronic® Polymer Solutions

The polymer was weighed into a plastic tube. To achieve the requiredconcentration the weight was multiplied by 4, for 25 weight percent (w%), and by 5, for 20 weight percent (w %), and the required final weightwas achieved by adding saline. The solutions were placed in the fridgeat 4° C. and usually were ready the next morning. Gelation points weremeasures in a Brookfield viscometer and the point at which viscosityexceeded the range of the plate/cone (>102,000 cP) was called thegelation temperature.

TABLE 1 Gelation Temperature of Selected Inverse Thermosensitive PolymerSolutions in Saline Polymer Concentration Temperature Tetronic 1107 25 w% 27° C. Tetronic 1107 20 w % 34° C. Purified Tetronic 1107 25 w % 22°C. Purified Tetronic 1107 20 w % 32.5° C.   Tetronic 1307 25 w % 24.5°C.   Tetronic 1307 20 w % 31° C. Purified Tetronic 1307 25 w % 20° C.Purified Tetronic 1307 20 w % 26° C. Pluronic F108 25 w % 26° C.Pluronic F108 20 w % 60° C. Purified Pluronic F108 25 w % 19° C.Purified Pluronic F108 20 w % 26

Example 2 Gelation Temperature of Selected Pluronic® and Tetronic®Polymer Solutions with Iodinated Contrast Agent

Purified polymers were weighed into 50 mL centrifuge tubes and a 1:1mixture of saline and 100% Omnipaque 300 were added until a specificweight percentage was reached. Gelation points were measured in aBrookfield viscometer and the point at which the viscosity exceeded therange of the plate/cone (>102,000 cP) was called the gelation point. Allsolutions were further heated to 37° C. to ascertain that the materialstill exceeded the viscosity range and remained a gel. All gels passed.

TABLE 2 Gelation Temperature of Purified Inverse Thermosensitive PolymerSolutions containing 50 w % Omnipaque 300 Polymer ConcentrationTemperature Purified Tetronic 1107 20 w % 24° C. Purified Tetronic 130721 w % 26.5° C.   Purified Tetronic F108 18 w % 21.5° C.   PurifiedTetronic F127 18 w % 18° C.

Example 3 Plastic Tube Experiments

A plastic tube with an inner diameter of 0.9 cm was used as a mimic of aureter. The tube was partially filled with saline and the kidney stoneplaced into the middle of the tube. A ureteroscope was placed inside thetube close to the stone and cold polymer solutions were injected behindthe stone. The stone was fragmented using either electro-hydrauliclithotripsy or laser lithotripsy. Various inverse thermosensitivepolymer solutions such as purified Pluronic F108 (poloxamer 338),Pluronic F127 (poloxamer 407) and Tetronic 1307, were tested in thisset-up in concentrations ranging from 15 to 25 w %. In all cases, thestone could be fragmented into smaller particles and the gel capturesall fragments. The lower polymer concentrations (15 w %) resulted inrather soft gels, while the higher polymer concentrations (25 w %) weredifficult to deploy due to the increased viscosity of the polymersolution and early onset of gelation.

Example 4 Pig Ureter Experiments

Pig ureters (approximately 25 cm in length) were fixed to a tray and thetray submerged in a water bath heated to 37° C. A sheath was insertedinto the ureter and a small (approximately 5 mm) Plaster of Paris kidneystone mimic was advanced into the ureter through the sheath using astone basket. A 3F catheter was advanced through the working channel ofthe ureteroscope approximately 3 cm behind the stone and 1.5 mL of a 20w % purified Pluronic F127 (poloxamer 407) solution was injected. Thepoloxamer gel was colored blue with methylene blue. Irrigation of theureter was accomplished with room temperature saline at a flow rate ofapproximately 5 mL/minute. Very little dilution of the gel was observedduring the 20 minutes of irrigation as the gelation temperature of thegel is about 15° C. Dissolution was easily accomplished by injectioninto the gel with either room temperature saline or cold water. The coldwater required less volume to dissolve the gel than the room temperaturesaline (20 mL vs. 35 mL).

Example 5 In Vivo Experiments

Independently two adult female pigs were anesthetized. In each a lowermidline incision was made, the left ureter isolated, a ureterotomyperformed adjacent to the bladder and a guide wire was advanced up theureter to the kidney. A stone was then pushed up the ureter toapproximately 10 cm proximal to the ureterotomy. A rigid ureteroscope(Stortz) was passed up the ureter, the stone visualized, a 3 Frenchcatheter passed through the ureteroscope beyond the stone, a cooled 20 w% solution of purified poloxamer 407 injected, the catheter removed andthe electro hydraulic probe passed to the stone through theureteroscope. The stone was successfully fragmented with no fragmentsprogressing proximally. The ureter was surgically removed, andpathological examination revealed a reactive epithelium consistent withmanipulation by the ureteroscope. The animals were euthanized. In sum,in both experiments, the stones were successfully fragmented without anydiscernable untoward effects to the ureters.

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. patent application publications citedherein are hereby incorporated by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed is:
 1. A method of mitigating risk of damage tosurrounding body tissue during lithotripsy on a concretion located in alumen of the body, the method comprising: introducing a solutioncomprising an inverse thermosensitive polymer at a location distal theconcretion in the lumen; forming a temporary plug in the lumen bygellation of the solution; deploying an energy source proximate to theconcretion on the opposite side of the concretion relative to thelocation of the temporary plug in the lumen; and applying energy to theconcretion with the energy source sufficient to fragment the concretionand propel one or more fragments of the concretion into the temporaryplug; wherein the temporary plug is configured such that it is capableof withstanding impact with fragments of the concretion and preventfurther migration of the fragments down the lumen beyond the location ofthe temporary plug, wherein the inverse thermosensitive polymer is apurified poloxamer or poloxamine.
 2. The method of claim 1, wherein saidinverse thermosensitive polymer is selected from purified poloxamine1107, purified poloxamine 1307, purified poloxamer 338 and purifiedpoloxamer
 407. 3. The method of claim 2, wherein said compositioncomprising an inverse thermosensitive polymer further comprises acontrast-enhancing agent.
 4. The method of claim 3, wherein saidcontrast-enhancing agent is selected from the group consisting ofradiopaque materials, paramagnetic materials, heavy atoms, transitionmetals, lanthanides, actinides, dyes, and radionuclide-containingmaterials.